Amyloid beta (Aβ), a principle component of the cerebral plaques found in the brains of patients with Alzheimer's disease (AD), is a pivotal factor implicated in the pathogenesis of AD. Recent reports show that not only extracellular Aβ but also intracellular Aβ induces neuronal apoptosis; however, the mechanism remains to be elucidated. Using yeast two-hybrid assays, we found that Aβ interacts with HtrA2/Omi, an essential human serine protease with proapoptotic activity. Additionally, we mapped the C-terminal region containing the PDZ domain of HtrA2/Omi as the binding determinant for Aβ? The interaction of Aβ with HtrA2/Omi was further confirmed through in vivo co-immunoprecipitation assay in HEK293 cells. This study suggests the possibility that the accumulation of intracellular Aβ and a function of proapoptotic protease, HtrA2/Omi are correlated.